Prostate cancer (PCa) is now the second leading cause of cancer deaths in males. Unfortunately, the pathogenesis of PCa remains unknown. The diagnosis, treatment, and prevention of PCa are major areas of concern. New approaches are required to address this major health problem. Important fundamental information concerning normal and neoplastic prostate is still lacking which contributes to the slow progress in dealing with PCa. The most significant metabolic and functional characteristic of normal and malignant prostate is associated with citrate metabolism. Normal prostate has the unique function of producing and secreting enormous levels of citrate, and normal prostate secretory epithelial cells are citrate producing cells. In contrast, in PCa the malignant epithelial cells have undergone a transformation to citrate oxidizing cells. Evidence now exists that m-aconitase is the key reaction in this metabolic transformation. Recent evidence demonstrates that prolactin and testosterone are involved in the regulation of m-aconitase in targeted prostate epithelial cells. In addition, zinc appears to be a major factor in the regulation of prostate m-aconitase activity and citrate oxidation. This proposed project will establish the mechanisms by which prolactin and testosterone regulate the biosynthesis of m-aconitase. The role and mechanism of zinc as an inhibitor of m-aconitase activity in prostate cells will be elucidated. These relationships will be established by studies with rat prostate lobes. Once this information is obtained, the role of prolactin, testosterone, and zinc in human malignant cells (LNCaP, PC-3, Du-145) will be determined. These will represent the first concerted studies concerning the regulatory factors associated with citrate-related metabolism of human prostate cells. Our broad long-term objectives are to understand the unique metabolic relationships associated with citrate metabolism of normal and neoplastic prostate; to establish the relationship of altered citrate metabolism to the process of prostate epithelial cell malignancy; to establish the important regulatory agents and mechanisms which are involved in the citrate-related metabolic transformation of nonmalignant citrate producing cells to malignant citrate oxidizing cells. This information will provide new insights into the pathogenesis of PCa and the malignant process and will provide new approaches to the diagnosis, prevention, and treatment of PCa.